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Endogenous Glucocorticoid Receptor Activation Modulates Early-Stage Cell Differentiation in Pancreatic Progenitors of Mice and Humans

ABSTRACT: Understanding the pancreatic developmental process is instrumental to tackle diabetes, allowing improvements of in vitro differentiation protocols aimed at producing of functional β-cells for transplantation. Here, we investigate the role of Glucocorticoid Receptor (GR) signaling in the earliest stages of pancreas development decisions in both mice and humans. Previous reports suggest that glucocorticoids do not play a significant role in mouse pancreas development before the second transition. In this study, we demonstrate that, under physiological conditions, the GR is selectively active in pro-acinar cells of the mouse embryonic pancreas from E11.5 and on. It is silenced in early-stage bipotent and endocrine progenitors, and its expression is reactivated upon endocrine commitment. Ectopic GR activation in mouse pancreatic explants globally commits progenitors to the acinar lineage. In sharp contrast, GR activation in in vitro-derived human pancreatic multipotent progenitors promotes commitment to the endocrine lineage, inducing the expression of novel genes associated with human embryonic pancreatic bipotential and endocrine progenitors. A combined epigenomic and single-cell transcriptomic screen suggests that these novel marker genes could play important roles in human pancreas development. Taken together, our findings position the GR pathway as an endogenous developmental modulator of early-stage pancreatic progenitor cell differentiation. We also demonstrate that glucocorticoids can bias in vitro-derived human pancreatic progenitor cell commitment toward the endocrine lineage and provide insights into the underlying transcriptional mechanisms potentially involved.

ORGANISM(S): Homo sapiens

PROVIDER: GSE237280 | GEO | 2025/04/30

REPOSITORIES: GEO

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Project description:deBack2012 - Lineage Specification in Pancreas Development This model of two neighbouring pancreas precursor cells, describes the exocrine versus endocrine lineage specification process. To account for the tissue scale patterns, this couplet model has been extended to hundreds of coupled cells. This model is described in the article: On the role of lateral stabilization during early patterning in the pancreas de Back W., Zhou JX, Brusch L J. R. Soc. Interface 6 February 2013 vol. 10 no. 79 20120766 Abstract: The cell fate decision of multi-potent pancreatic progenitor cells between the exocrine and endocrine lineages is regulated by Notch signalling, mediated by cell–cell interactions. However, canonical models of Notch-mediated lateral inhibition cannot explain the scattered spatial distribution of endocrine cells and the cell-type ratio in the developing pancreas. Based on evidence from acinar-to-islet cell transdifferentiation in vitro, we propose that lateral stabilization, i.e. positive feedback between adjacent progenitor cells, acts in parallel with lateral inhibition to regulate pattern formation in the pancreas. A simple mathematical model of transcriptional regulation and cell–cell interaction reveals the existence of multi-stability of spatial patterns whose simultaneous occurrence causes scattering of endocrine cells in the presence of noise. The scattering pattern allows for control of the endocrine-to-exocrine cell-type ratio by modulation of lateral stabilization strength. These theoretical results suggest a previously unrecognized role for lateral stabilization in lineage specification, spatial patterning and cell-type ratio control in organ development. This model is hosted on BioModels Database and identified by: MODEL1211010000 . To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models . To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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Endogenous Glucocorticoid Receptor Activation Modulates Early-Stage Cell Differentiation in Pancreatic Progenitors of Mice and Humans

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